Oral tolerance to food proteins is thought to develop in the small intestine. Here, food antigens are taken up and transferred to CD103+ dendritic cells (DCs) that then migrate to the mesenteric lymph nodes where they induce the generation of antigen-specific T regulatory cells (Tregs). Tregs are characterized by expression of the transcription factor, Foxp3, and play a key role in suppressing T helper 2 effector (Th2) immune responses to innocuous food antigens. In mice, adoptive transfer of antigen-specific Tregs can protect against food-induced anaphylaxis after establishment of allergic sensitization. Mice that lack peripherally-induced Tregs spontaneously develop Th2 inflammation in the GI tract and antibodies to food proteins in mouse chow. Both mice and humans with mutations in FOXP3 are more likely to develop allergic disease. Food allergy, therefore, is thought to result from a failure to establish or maintain oral tolerance. To further interrogate the role for T cells in the pathogenesis of food allergy, we have developed a novel assay that allows us to simultaneously detect peanut-specific Tregs and T effector cells. Peanut allergy is the number one cause of allergic reactions in the United States, and the prevalence appears to be increasing at an alarming rate. Using this assay, we are examining the cytokine expression profile, pattern of homing receptor expression, and epigenetic signatures that distinguish peanut-specific T cells in children with and without peanut allergy, and how they change in allergic children who eventually acquire tolerance. No FDA-approved treatment for food allergy is currently available. Recent studies suggest that oral immunotherapy (OIT), in which the allergenic food is mixed into a vehicle and then ingested in gradually increasing quantities, may hold promise as a potential treatment for food allergy. However, excitement for this therapy has been tempered by the frequent occurrence of side effects, including severe allergic reactions, and the lack of sustained protection in most subjects once treatment is discontinued. These limitations have sparked investigations into adjunctive therapies, including omalizumab, that would improve both safety and long-term efficacy. Omalizumab is a humanized monoclonal antibody that sequesters free IgE and prevents its binding to the high affinity IgE receptor FcRI. Results of the first double-blind placebo-controlled (DBPC) trial of omalizumab in combination with OIT in patients with severe persistent milk allergy were recently reported. Although omalizumab did not significantly improve the rates of desensitization compared to subjects receiving milk OIT (MOIT) alone, omalizumab-treated subjects exhibited significant improvements in nearly all safety parameters. We are now working to dissect the effects of omalizumab on basophil and T cell allergen-induced activation in subjects undergoing MOIT, and to explore whether baseline biomarkers can predict which subjects are likely to benefit the most from adjunctive treatment with omalizumab.